Hypokalemia

Question 1

Clinical Manifestations

Answer 1

Muscle weakness, rhabdomyolysis, fatigue, ileus, constipation, leg cramps, respiratory difficulty ECG changes: U waves, T-wave flattening, ST-segment depression, arrhythmias, asystole Nephrogenic diabetes insipidus, hypokalemic nephropathy

Question 2

Clinical Manifestations 40% of patients with hypokalemia also have hypomagnesemia: possible mechanisms:

Answer 2

Underlying abnormality/pathology can cause both (e.g., cisplatin, amphotericin, diuretics use, poor dietary intake, diarrhea) Mg2+ is a gate-keeper for ROMK. Low Mg2+ level leaves ROMK open, thus K+ wasting

Question 3

Clinical Manifestations 40% of patients with hypokalemia also have hypomagnesemia: possible mechanisms:

Answer 3

Mg2+ is a cofactor in Na+-K+-ATPase, H+-K+-ATPase Enhanced aldosterone state leading to renal wasting of both cations.

Question 4

Causes and Mechanisms of Hypokalemia Pseudohypokalemia

Answer 4

In vitro (test tube) hypokalemia, not in vivo hypokalemia Pseudohypokalemia may be seen in patients with acute (or chronic) myeloid leukemia due to continuing cellular K+ uptake into rapidly proliferating cells even after the blood is drawn. There may be associated pseudohypoglycemia and hypophosphatemia.

Question 5

Causes and Mechanisms of Hypokalemia Pseudohypokalemia

Answer 5

Seasonal pseudohypokalemia: due to increased intracellular K+ uptake via increased Na+-K+-ATPase activity with transport of blood tubes in warm ambient temperatures

Question 6

Causes and Mechanisms of Hypokalemia Pseudohypokalemia

Answer 6

Question 7

Causes and Mechanisms of Hypokalemia

Decreased K+ Input

Answer 7

Inadequate dietary intake, severe malnutrition (rare due to kidneys’ ability to minimize K+ loss to 5 to 20 mEq/L)

Clay ingestion “geophagia.” Clay binds K+.

Question 8

Causes and Mechanisms of Hypokalemia

Increased Bodily K+ Loss/Output

Answer 8

Gastrointestinal loss: severe diarrhea, vomiting3/nasogastric suction, bowel cleansing (phenolphthalein laxatives, sodium polystyrene sulfonate), acute colonic obstruction, Ogilvie syndrome (acute colonic pseudo-obstruction associated with a secretory diarrhea with very high K+content due to activation of colonic K+ secretion. This condition is associated with various acute illnesses/stressors. Associated electrolyte abnormalities include hypokalemia, hypomagnesemia, and hypocalcemia).

Question 9

Causes and Mechanisms of Hypokalemia

Increased Bodily K+ Loss/Output

Answer 9

Excessive sweats, extensive burns

Dialysis, plasmapheresis

Urinary loss

Question 10

Causes and Mechanisms of Hypokalemia

Intracellular K+ Shift Due to Increased Extracellular pH

Answer 10

Increased extracellular pH (e.g., metabolic or respiratory alkalosis) leads to K+ shifting into cells in exchange for H+ efflux to reduce the extracellular pH.

Question 11

Causes and Mechanisms of Hypokalemia

NOTE

Answer 11

In patients with severe hypokalemia and metabolic acidosis (e.g., patient with proximal RTA), replace K+ to safe level prior to alkalinization!!!

Question 12

Causes and Mechanisms of Hypokalemia

Intracellular K+ Shift Due to Increased Extracellular pH

Answer 12

Increased Na+-K+-ATPase activity:

Insulin administration or endogenous insulin release with glucose administration (e.g., dextrose 5% saline solution)

Question 13

Causes and Mechanisms of Hypokalemia

Intracellular K+ Shift Due to Increased Extracellular pH

Answer 13

NOTE

In diabetic patients with poorly controlled glucose and preexisting life-threatening hypokalemia, provide K+ replacement prior to insulin administration to avoid further fall in preexisting low S[K+]!!!

Question 14

Causes and Mechanisms of Hypokalemia

Intracellular K+ Shift Due to Increased Extracellular pH

Answer 14

Increased β2-adrenergic activity increases cellular K+ uptake: stress, coronary ischemia, delirium tremens, thyroid hormone, β2-agonists (albuterol, terbutaline, dopamine, dobutamine, pseudoephedrine), sympathomimetic stimulants (e.g., amphetamines, high-dose caffeine), theophylline toxicity.

Question 15

Causes and Mechanisms of Hypokalemia

Intracellular K+ Shift Due to Increased Extracellular pH

Answer 15

Inhibition of ATP-dependent K+ channels blocks K+ efflux during repolarization: hypothermia, barium/cesium poisoning, chloroquine intoxication.

Question 16

Causes and Mechanisms of Hypokalemia

Question 17

Causes and Mechanisms of Hypokalemia

Hypokalemic periodic paralysis:

Answer 17

Rare channelopathy (autosomal dominant, varying penetrance):

90% with mutation of the α1-subunit of dihydropyridine-sensitive Ca2+ channel; 10% with mutation of the skeletal muscle Na+ (SCN4A) channel.

Question 18

Causes and Mechanisms of Hypokalemia

Hypokalemic periodic paralysis:

Answer 18

Muscle weakness or paralysis in association with a fall in S[K+]

Upper > lower extremity; proximal > distal weakness

May be associated with hypophosphatemia and hypomagnesemia

Question 19

Causes and Mechanisms of Hypokalemia

Hypokalemic periodic paralysis:

Answer 19

Attacks often begin in adolescence

Triggered by strenuous exercise followed by rest; high-carbohydrate and high-sodium meals or administration of glucose, insulin, or glucocorticoids; sudden changes in temperature, excitement, loud noise, or flashlights

Question 20

Causes and Mechanisms of Hypokalemia

Hypokalemic periodic paralysis:

Associated conditions:

Answer 20

Andersen syndrome: periodic paralysis occurring with either hypo- or hyperkalemia; associated with prolonged QT and sudden death

Thyrotoxicosis due to Graves disease: more common in Asian or Latin/Native American males (propranolol may reverse attacks pending definitive therapy). Of note, patients with thyrotoxicosis hypokalemia periodic paralysis may also have elevated bone alkaline phosphatase for unclear reason.

Question 21

Causes and Mechanisms of Hypokalemia

Hypokalemic periodic paralysis:

Answer 21

Diagnosis: Electromyograms during attacks or with exercise

Question 22

Causes and Mechanisms of Hypokalemia

Hypokalemic periodic paralysis:

Treatment:

Answer 22

Potassium supplement (slow and low dose due to rebound)

If can swallow and breathe adequately: oral KCl, K-citrate, or K-bicarbonate 15 to 30 mEq in 30- to 60-minute intervals as needed.

Question 23

Causes and Mechanisms of Hypokalemia

Hypokalemic periodic paralysis:

Answer 23

If cannot swallow and life-threatening: KCl 15 mEq over 15 minutes, then 10 mEq/h in 500 mL dilutant; 5% mannitol dilutant is preferred over normal saline (sodium may worsen condition). Never use glucose (due to endogenous insulin secretion and exacerbation of hypokalemia).

Question 24

Causes and Mechanisms of Hypokalemia

Hypokalemic periodic paralysis:

Answer 24

Cardiac monitoring is required with intravenous KCl administration.

Prevention: β2-blockers, K+ supplement, low carbohydrate diet, K+-sparing diuretics, CA inhibitor (acetazolamide)

Question 25

Causes and Mechanisms of Hypokalemia Increased Renal K+ Loss

Answer 25

Recall renal K+ secretion depends on: (1) distal Na+ delivery, (2) generation of transepithelial potential difference (negative lumen) via Na+ entry into ENaC in principal cells at aldosterone-sensitive distal nephron segment, (3) distal urine flow, (4) presence of aldosterone, (5) sensitivity to aldosterone, and (6) kidney mass

Question 26

Causes and Mechanisms of Hypokalemia Enhanced renal K+ secretion occurs with:

Answer 26

Increased distal Na+ delivery to cortical and corticomedullary collecting tubules: - Diuretics, high fluid intake/intravenous fluid infusion - Bartter and Gitelman syndromes

Question 27

Causes and Mechanisms of Hypokalemia Generation of transepithelial potential difference (negative lumen) via Na+ entry into ENaC in principal cells at aldosterone-sensitive distal nephron segment is increased:

Answer 27

Liddle syndrome Autosomal dominant, gain-of-function mutation in the β- and γ-subunits of ENaC (PY motif) that reduces the “housekeeping” recognition of ENaC by Nedd4-2 for internalization and degradation, resulting in an increased number of functioning apical ENaC.

Question 28

Causes and Mechanisms of Hypokalemia Generation of transepithelial potential difference (negative lumen) via Na+ entry into ENaC in principal cells at aldosterone-sensitive distal nephron segment is increased: Liddle syndrome:

Answer 28

Affected patients present with HTN due to excess Na+ retention; hyporenin, hypoaldosteronism due to volume expansion; but hypokalemia and metabolic alkalosis due to facilitated renal K+ and H+ secretion following increased Na+ entry into the undegraded apical ENaC. Treatment: ENaC inhibition with amiloride. Since this is an end-organ defect, kidney transplantation is curative.

Question 29

Causes and Mechanisms of Hypokalemia Generation of transepithelial potential difference (negative lumen) via Na+ entry into ENaC in principal cells at aldosterone-sensitive distal nephron segment is increased:

Answer 29

Nonreabsorbable anions delivery to collecting tubules can enhance K+ secretion due to the favorable electrical gradient. Additionally, the increased Na+ delivery associated with the anions will also enhance the generation of the favorable electrochemical gradient for K+secretion.

Question 30

Causes and Mechanisms of Hypokalemia Generation of transepithelial potential difference (negative lumen) via Na+ entry into ENaC in principal cells at aldosterone-sensitive distal nephron segment is increased:

Answer 30

Examples of nonreabsorbable anions: bicarbonate (vomiting and proximal RTA), β-hydroxybutyrate in diabetic ketoacidosis, high-dose penicillin/penicillin derivative administration, hippurate from toluene with glue sniffing.

Question 31

Causes and Mechanisms of Hypokalemia Enhanced renal K+ secretion occurs with:

Answer 31

High distal urine flow: high volume intake/infusion, diuretics Increased mineralocorticoid activity

Question 32

Causes and Mechanisms of Hypokalemia Increased Renal K+ Loss Increased mineralocorticoid activity

Answer 32

Clinical manifestations: classically seen with triad of hypertension, hypokalemia, and metabolic alkalosis Mineralocorticoid excess may be categorized as aldosterone dependent, cortisol dependent, or non-aldosterone, non-cortisol dependent

Question 33

Causes and Mechanisms of Hypokalemia Increased Renal K+ Loss Increased mineralocorticoid activity Aldosterone dependent:

Answer 33

Secondary aldosteronism: High renin level leads to aldosterone synthesis. Source of renin: hypoxia-induced (renovascular hypertension) or unregulated synthesis (renin-secreting tumors)

Question 34

Causes and Mechanisms of Hypokalemia Increased Renal K+ Loss Increased mineralocorticoid activity Aldosterone dependent: Primary aldosteronism:

Answer 34

Aldosterone synthesis is independent of renin levels. Sources of aldosterone: adrenal hyperplasia, adenoma, or carcinoma, glucocorticoid-remediable aldosteronism

Question 35

Causes and Mechanisms of Hypokalemia Increased Renal K+ Loss Increased mineralocorticoid activity Aldosterone dependent: Primary aldosteronism: Glucocorticoid-remediable aldosteronism:

Answer 35

Autosomal dominant with formation of a chimeric gene due to unequal crossover of sequences at meiosis, where the hybrid gene contains both the promoter of 11-β-hydroxylase enzyme (enzyme for cortisol synthesis) and aldosterone synthase gene (enzyme for aldosterone synthesis)

Question 36

Causes and Mechanisms of Hypokalemia Increased Renal K+ Loss Increased mineralocorticoid activity Aldosterone dependent: Primary aldosteronism: Glucocorticoid-remediable aldosteronism:

Answer 36

Stimulation of the promoter with ACTH upregulates both cortisol and aldosterone synthesis. Recall that aldosterone is normally upregulated by angiotensin II.

Question 37

Causes and Mechanisms of Hypokalemia Increased Renal K+ Loss Increased mineralocorticoid activity Aldosterone dependent: Primary aldosteronism: Glucocorticoid-remediable aldosteronism:

Answer 37

Clinical manifestations: early moderate to severe HTN, hemorrhagic stroke and ruptured aneurysms (brain MRA every 5 years after puberty has been recommended), normo- to hypokalemia (the former due to the diurnal variation of ACTH).

Question 38

Causes and Mechanisms of Hypokalemia Increased Renal K+ Loss Increased mineralocorticoid activity Aldosterone dependent: Primary aldosteronism: Glucocorticoid-remediable aldosteronism:

Answer 38

Diagnosis: genetic testing for crossover between aldosterone-synthetase and 11-β-hydroxylase; biochemical evaluation: suppressed plasma renin activity and high serum aldosterone, increased levels of 18-hydroxy-cortisol, ACTH and 18-oxo-cortisol.

Question 39

Causes and Mechanisms of Hypokalemia Increased Renal K+ Loss Increased mineralocorticoid activity Aldosterone dependent: Primary aldosteronism: Glucocorticoid-remediable aldosteronism:

Answer 39

Treatment: glucocorticoid (to suppress ACTH) or mineralocorticoid receptor antagonism (spironolactone, eplerenone) ± ENaC antagonism (amiloride) to counteract the effect of excess aldosterone.

Question 40

Causes and Mechanisms of Hypokalemia Increased Renal K+ Loss Increased mineralocorticoid activity Cortisol dependent: (cortisol has mineralocorticoid activity)

Answer 40

Sources of cortisol: excess production (Cushing’s); reduced inactivation of cortisol to cortisone by the enzyme 11-β-hydroxysteroid dehydrogenase type 2 11-βHSD2).

Question 41

Causes and Mechanisms of Hypokalemia Increased Renal K+ Loss Increased mineralocorticoid activity Cortisol dependent: (cortisol has mineralocorticoid activity)

Answer 41

Reduced 11-β-hydroxysteroid dehydrogenase activity: - Licorice: glycyrrhizic acid and its hydrolytic product, glycyrrhetinic acid, from licorice are potent competitive inhibitors of 11-βHSD2. - Mutation of 11-βHSD2: Syndrome of apparent mineralocorticoid excess (AME)

Question 42

Causes and Mechanisms of Hypokalemia Increased Renal K+ Loss Increased mineralocorticoid activity Non-aldosterone, non-cortisol dependent:

Answer 42

- Liddle syndrome - Deoxycorticosteroid excess (associated with congenital adrenal hyperplasia)

Question 43

Causes and Mechanisms of Hypokalemia Increased Renal K+ Loss Increased mineralocorticoid activity Non-aldosterone, non-cortisol dependent:

Answer 43

Activating mutation of mineralocorticoid receptor (MR): - Autosomal dominant disorder where the MR is constitutively activated - Hypertension may worsen with pregnancy due to progesterone - Spironolactone (normally an MR antagonist) now acts as an agonist!

Question 44

Causes and Mechanisms of Hypokalemia Evaluation of Mineralocorticoid Excess in patients with Triad of HTN, Hypokalemia, and Metabolic Alkalosis:

Answer 44

Question 45

Causes and Mechanisms of Hypokalemia Others Amphotericin B:

Answer 45

This is a multiplanar molecule that is lipophilic on the outside and hydrophilic on the inside. The molecule inserts itself into tubular cell membrane and acts as an ionophore, allowing electrolytes to flow in the direction of favorable chemical gradient.

Question 46

Causes and Mechanisms of Hypokalemia Others Amphotericin B:

Answer 46

The formulation of liposomal amphotericin covers up the lipophilic surface of amphotericin and reduces its insertion into tubular membranes, thus minimizing intracellular electrolyte losses into the urinary space and back-leak of H+ into circulation.

Question 47

Causes and Mechanisms of Hypokalemia Others Amphotericin B

Answer 47

Question 48

Causes and Mechanisms of Hypokalemia Others

Answer 48

Magnesium deficiency can lead to K+ wasting at the thick ascending limb of loop of Henle. Mg2+ is a “gate-keeper” against K+ exit via ROMK into the lumen.

Question 49

Causes and Mechanisms of Hypokalemia Others

Answer 49

Salt-wasting nephropathies, tubular injuries (tubulointerstitial diseases, cisplatin, aminoglycosides), acute monocytic or myelomonocytic leukemia with lysozyme-induced tubular injury leading to K+ wasting)

Question 50

Causes and Mechanisms of Hypokalemia Others

Answer 50

Hypercalcemia (inhibits ROMK in thick ascending limb of loop of Henle and induces a form of nephrogenic diabetes insipidus).

Question 51

Causes and Mechanisms of Hypokalemia Others Management of Hypokalemia: Routine Considerations

Answer 51

If S[K+] \< 3 mEq/L, STAT ECG, cardiac monitor If safe, avoid glucose-containing solutions until life-threatening hypokalemia has been corrected.

Question 52

Causes and Mechanisms of Hypokalemia Others Management of Hypokalemia: Routine Considerations

Answer 52

If safe, avoid correction of hyperglycemia with insulin administration until life-threateninghypokalemia has been corrected. If safe, avoid alkalinization until life-threatening hypokalemia has been corrected.

Question 53

Causes and Mechanisms of Hypokalemia Others Management of Hypokalemia: Routine Considerations

Answer 53

Use central lines if \>10 mEq/h replacement is needed. Consider femoral line over internal jugular or subclavian line if \>20 mEq/h replacement is needed to avoid cardiac irritation. Check magnesium levels and replace as necessary.